A survey of patient and physician acceptance of skin toxicities … · 2018-02-21 ·...

ORIGINAL ARTICLE

A survey of patient and physician acceptance of skin toxicitiesfrom anti-epidermal growth factor receptor therapies

Bernd Tischer1 & Martina Bilang1 & Matthias Kraemer2 & Philippe Ronga2 &

Mario E. Lacouture3

Received: 20 July 2017 /Accepted: 23 October 2017 /Published online: 7 November 2017# The Author(s) 2017. This article is an open access publication

AbstractBackground Inhibition of the epidermal growth factor recep-tor (EGFR) extends patient survival in multiple tumor types.Skin toxicities are the most common adverse event (AE) elic-ited by EGFR inhibitors. Here, we provide deeper insightsinto patients’ and physicians’ acceptance of the risk/benefittrade-offs of skin toxicities during cancer therapy, includingcomparison of their perceptions and experiences with derma-tologic AEs.Methods Amultinational survey of 195 patients and 120 physi-cians was conducted to gauge attitudes regarding skin toxicitiesas an AE during cancer therapy.Results Skin toxicities were identified by patients and physi-cians as the AE that is most discouraging to patients whenundergoing cancer therapies. Skin toxicities were cited as

causing pain, impairing quality of life, and proving difficultto manage. Despite these negative influences, the majority ofpatients (71%) indicated they were willing to accept skin tox-icities as an AE of an effective therapy. Indeed, the majority ofpatients and physicians preferred a more effective therapy thatinduces more severe skin toxicities than a less efficacioustherapy that induces less severe skin toxicities; interestingly,patients were willing to accept a higher likelihood of severeskin toxicities than physicians.Conclusion In this examination of patients’ perspectives, wefound that patients were willing to accept skin toxicities if theywere the anticipated byproduct of a more effective therapeuticregimen. Important differences were observed between pa-tients’ and physicians’ attitudes regarding risk/benefit trade-offs during cancer therapy, suggesting that patient’s consider-ations and shared decision-making are key to cancer care.

Keywords EGFR inhibitors . Skin toxicity . Patientperspective . Survey

Introduction

Epidermal growth factor receptor (EGFR) inhibition is anestablished, effective therapeutic option for patients with co-lorectal cancer (CRC) [1], squamous cell carcinoma of thehead and neck (SCCHN) [2], lung cancer [3, 4], and pancre-atic cancer [5]. Many EGFR inhibitors are approved for clin-ical use, including monoclonal antibodies (e.g., cetuximab,necitumumab, and panitumumab) and tyrosine kinase inhibi-tors (including afatinib, erlotinib, gefitinib, lapatinib, andosimertinib). Many of these agents are standard-of-care treat-ments acrossmultiple indications. Although EGFR inhibitorsimprove patient survival, they are also associated with skintoxicities. Indeed, the most common adverse event (AE)

Electronic supplementary material The online version of this article(https://doi.org/10.1007/s00520-017-3938-7) contains supplementarymaterial, which is available to authorized users.

* Mario E. [email protected]

Bernd [email protected]

Martina [email protected]

Matthias [email protected]

Philippe [email protected]

1 Kantar Health, Munich, Germany2 Merck KGaA, Darmstadt, Germany3 Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New

York, NY 10065, USA

Support Care Cancer (2018) 26:1169–1179https://doi.org/10.1007/s00520-017-3938-7

https://doi.org/10.1007/s00520-017-3938-7

mailto:[email protected]

http://crossmark.crossref.org/dialog/?doi=10.1007/s00520-017-3938-7&domain=pdf

attributable to EGFR inhibitors is mild to moderateacneiform rash, but it can be severe in up to 18% of patients[6–8]. EGFR inhibitor-elicited skin toxicities begin as ede-ma and erythema during the first weeks of therapy, followedby acneiform eruptions and crusting, and ultimatelyparonychia and fissure [9, 10]. Other dermatologic AEs(dAEs) that can accompany EGFR inhibitor therapy includeskin aging, xerosis, hair changes, and pruritus [11–13].These skin toxicities can be painful and debilitating, there-by potentially affecting patients’ quality of life (QoL) andadherence to therapy [12–16].

The most widely used grading method is the NationalCancer Institute Common Terminology Criteria for AdverseEvents version 4.0 (NCI-CTCAE v4.0) itself, which catego-rizes skin toxicities as grades 1–5 based on a definedphysician-assessed scoring system that takes into account thepercentage of the body that is impacted [17]. Therefore, thismethodwas used to evaluate skin toxicities in this survey, witha simplified scale including only grades 1 to 3, because grade4 and 5 events are extremely rare.

A previously performed structured literature search re-vealed an unmet need for research regarding the influence ofdAEs on patients’ QoL and their acceptance of cancer treat-ments [18]. Specifically, systematic studies that compare theimpact of dAEs vs other AEs on therapeutic decisions frompatients’ and physicians’ perspectives were identified as ab-sent. Accordingly, the purpose of the present survey analysiswas to provide deeper insights into patients’ and physicians’acceptance of the risk of skin toxicities during cancer therapy,including a comparison of patients’ and physicians’ view-points and an examination of their perceptions regarding ac-ceptable risk/benefit trade-offs.

Methods

Survey design

The full patient and physician questionnaires are included inthe Online Supplemental Materials (Supplemental Figs. S1 andS2). During the interviews, two different perspectives on thedegree of skin rash severity were measured: those of physicians(standardized categorization per the guidelines) and of patients(perceived).

For the risk/benefit trade-off analysis, 192 patients wereasked to imagine a hypothetical scenario in which a newsecond-line therapy was available to treat their cancer. Thenew therapy was described to have better efficacy than cur-rently available alternatives, but was explicitly defined asnon-curative. However, the new therapy was also assumedto elicit severe skin toxicities for 6 to 8 weeks in a certainpercentage of patients; the skin toxicities were defined aspotentially impairing normal daily function. Given these

parameters, the patients were then asked whether theywould take the new therapy if the risk of severe skin toxic-ities was 0%. If they answered “yes,” the same question wasposed with the risk of severe skin toxicities now being 10%higher; the exercise was repeated (continuing to use 10%-increase intervals) until the respondents answered “no.”Physicians were asked to estimate the percentage of patientswho would accept a cancer therapy that causes severe skinrash at different risk levels.

Detailed methods and statistical analyses are described inthe supplemental material.

Results

Characteristics of the survey respondents

This multinational survey queried 195 patients with CRC,SCCHN, lung cancer, or pancreatic cancer in Europe and theUSA (Supplemental Table S1). Notably, 148/195 surveyedpatients had received an EGFR inhibitor (afatinib, cetuximab,erlotinib, gefitinib, and/or panitumumab) previously. Baselinecharacteristics between the EGFR inhibitor-experienced vsEGFR inhibitor-naïve groups (n = 47) of patients were similar,with the exception of the proportion of patients with lungcancer (65 vs 35% of patients, respectively) and(expectedly) the incidence of reported skin toxicities (90 vs55% of patients, respectively). Detailed baseline characteris-tics are described in the supplemental material.

Skin toxicities experienced by the 195 respondents includ-ed rash (67%), dryness (56%), itching (43%), brittle/ingrownnails (31%), inflammation around the nails (29%), skin colorchanges (29%), and unwanted hair growth (18%). For manypatients, skin toxicities had an impact on their activities ofdaily living (Fig. S1, Q34). Of the patients who experiencedskin toxicities (n = 158), 45% were fully active and able tocarry out daily activities, 39% were restricted in carrying outphysically strenuous activities, 11% were capable of walkingand self-care but not of working, and 5% were mostly/completely confined to a bed or chair. Of the 35 respondentswho experienced severe skin toxicities, 25 (71%) were fullyactive or only restricted from strenuous activity, and 10 (29%)were either unable to work (n = 4) or confined mostly/completely to a bed or chair (n = 6).

Among the 120 surveyed physicians (SupplementalTable S2), 68% were medical oncologists, who actively treat-ed an average of 322 cancer patients over the past 6 months,representing the following indications: (all advanced/metasta-tic) CRC (n = 66), SCCHN (n = 22), lung cancer (n = 70), andpancreatic cancer (n = 20), plus an average of 144 patientswith other cancer types actively managed over the past6 months.

1170 Support Care Cancer (2018) 26:1169–1179

Patients’ and physicians’ perspectivesregarding the impact of various AEs on patients’acceptance of cancer therapy

Of the 158 patients who experienced skin toxicities, 13% con-sidered stopping the therapy, and 7% followed through on thatdecision (Fig. S1, Q28). Similarly, physicians stopped thetreatment regimen in 10% of patients within the subgroupwho experienced skin toxicities despite maintaining anEastern Cooperative Oncology Group performance status(ECOG PS) of 0 or 1. Conversely, 84% of respondents whoexperienced skin toxicities (n = 158) said they would choosethe same therapy again, at similar rates between EGFRinhibitor-experienced and EGFR inhibitor-naïve patients (83and 85%, respectively). These findings suggest that althoughdAE-related QoL is important during cancer treatment, pa-tients are willing to tolerate skin and other toxicities in orderto continue treatment. Therefore, patient perspectives can beinformative to physicians and should thus be incorporated intoa shared decision-making model of therapy planning.

Interestingly, patients’ attitudes towards AEs can shift dur-ing the course of therapy (Fig. S1, Q21–22). Specifically, atdiagnosis, 59% of 195 respondents were willing to accept anytreatment regardless of AEs, whereas during or after therapy,15% of patients reported a reduced willingness to accept alltypes of AEs. Furthermore, 67% of patients who experienceddAEs (n = 158) reported that they would have accepted ahigher level of risk of skin toxicities at the time of first cancerdiagnosis than at the time they were interviewed for this study.

To gauge which AE(s) may be most discouraging to pa-tients in terms of accepting a cancer therapy, a paired-comparison exercise was performed. Of 195 surveyed pa-tients, skin toxicities (grade 3) and nausea/vomiting were sig-nificantly more impactful than fatigue and hair loss (p < .001)(Fig. 1a). Similarly, skin toxicities (grade 3) were significantlymore discouraging than nausea/vomiting, fatigue, and hairloss in the survey of 120 physicians (p < .001) (Fig. 1b).When asked to identify the source of unpleasant or negativeexperiences pertaining to their cancer therapy, nearly half(45%) of 148 survey respondents treated with an EGFR in-hibitor mentioned (severe) skin toxicities. In contrast, 10% ofEGFR inhibitor-experienced patients mentioned fatigue and7% mentioned nausea/vomiting. Taken together, these obser-vations suggest that skin toxicity is the AE that is most im-pactful to patients in terms of accepting a cancer therapy.

Patients’ and physicians’ perspective regarding why skintoxicities were rated as the most bothersome cancertherapy-related AE

Of the 159 patients included in the survey who had experi-enced skin toxicities as an AE associated with their cancertherapy, 47 patients (approximately 30%) identified skin

toxicities as the most bothersome AE compared to otherAEs. Of the 47 respondents, 40% rationalized their rankingdue to feeling bad, sick, or feeling discomfort; feelingashamed for esthetic reasons (28%), pain (26%), and impacton daily life (13%) were also commonly cited. Physicians,who rated skin toxicities as more discouraging than at leastone other AE when selecting a therapy to prescribe (n = 115),mentioned that being less manageable than other AEs andhaving an impact on patients’ QoL are the predominant rea-sons; similarly, 179 surveyed patients who rated skin toxicitiesas more discouraging than at least one other AE reported thatthey were principally discouraged by the impact on their QoL,the associated pain and the duration and extent of the skintoxicity (Table 1).

Patients’ perspective on experiencing skin toxicitiesand the impact of skin toxicities on daily living

Of 159 patients who experienced a skin toxicity, 67% initially(i.e., their first reaction to a skin toxicity occurring) had anegative perception (e.g., esthetic concerns, frustration, oranxiety), 35% reported a neutral position (they expected/understood that skin toxicities were likely to occur), and21% accepted the occurrence of skin toxicities as a conse-quence of their therapy (Table 2). Thus, the response todAEs was mixed, and many patients provided both positiveand negative statements about their initial experiences.Interestingly, in the survey of 120 physicians, when talkingwith their patients about skin toxicities as possible side effectsof their therapy, the rate of patients’ acceptance was perceivedto be much higher than it was in the self-reported patientsurvey (patients describing their reaction to the first appear-ance of skin toxicity, 63 vs 21%), where acceptancemeant thatskin toxicities were seen as a necessary part of therapy and nota predominant source of distress (Table 2; Fig. S1, Q26; Fig.S2, Q36). The 63% of physicians who described their patientsas accepting of dAEs proposed the wide availability of pre-ventative treatments and trust in the physician as justifications.Patients treated with EGFR inhibitors who experienced skintoxicities (n = 132) confirmed that dAEs had an impact onsocial-emotional and functional aspects of their lives(Table 3). Furthermore, 40% reported itching of the scalp,27% felt unattractive, 24% reported that their mood was af-fected, 22% felt embarrassed, 21% felt the skin toxicities in-terfered with their social life, and 19% avoided going out inpublic. Thus, patients felt that skin toxicities were bothersomefor a variety of reasons that impinge upon their QoL. Femalepatients reported significantly more often than males thatdAEs had an emotional or social impact (e.g., feeling unat-tractive, feeling embarrassed, skin condition interfered withsocial life, “I avoided going out in public”). Among the 35surveyed patients who experienced severe dAEs, nearly halfagreed that dAEs interfered with their social life. Furthermore,

Support Care Cancer (2018) 26:1169–1179 1171

> 40% felt unattractive and 29% reported that their ability tosleep was affected. Finally, the sensitivity of their fingernailsmade it difficult for one-third of the patients to perform house-hold tasks.

Interestingly, > 40% of surveyed physicians believed thatthe patients’ interpersonal interaction was the QoL social as-pect that was most affected. Additionally, 39% of physiciansfelt that dAEs affected patients’ desire to be with other people,21% agreed that dAEs led patients to tend to stay at home,31% believed that dAEs had an effect on patients’ work orhobbies, and 18% felt that dAEs made patients feel ashamed.Finally, 30% felt that skin toxicities affected patients’ sleep.

Physician-patient communication regarding skin toxicities

Of 195 surveyed patients, 71% felt well-informed about theircancer therapy; somewhat fewer patients (64%) felt well-informed about skin toxicities as a possible AE of cancertherapies. 4 and 9% of patients felt that they had not beensufficiently well-informed about their therapy and the poten-tial for skin toxicities, respectively. Notably, EGFR inhibitor-experienced patients felt significantly better informed about

skin toxicities than did EGFR inhibitor-naïve patients (70 vs45%, respectively; p = .001). In addition, 90% of the patientswho received EGFR inhibitor-based therapy reported that theyhad been informed regarding toxicities restricted to the skin asa possible AE, but only 46 and 38% had been warned ofpossible nail toxicities and hair toxicities, respectively. 92%of the 147 (1 patient did not answer the question) surveyedpatients who were treated with an EGFR inhibitor had heardor read information about skin toxicities as a possible AE oftheir therapy. Of these patients, 88% reported having beeninformed via conversations with doctors, whereas < 30% ofpatients indicated that they had been informed via the internet(28%), conversations with nurses (22%), other patients (20%),cancer brochures (17%), pharmaceutical companies (9%), apatient support community (6%), a magazine article (3%),friends/relatives (3%), or an information event for patients(1%) (Fig. 2).

Patient acceptance of skin toxicities

Of 195 surveyed patients, 85% agreed that a good QoL, de-spite receiving cancer therapy, is very important. Furthermore,

** **

** ** **

Skin rash

More discouraging (% of resp.)

Complete hair loss

Complete hair loss

Skin rash7128

7624

7623


5047

Skin rash


7723


6633Complete hair loss

More discouraging (% of resp.) More discouraging (% of resp.)

Itching or painful skin rash covering >30% of the BS including face for several weeks with lack of energy for several weeks

sever rapy veral daysComplete hair loss

Q16: Paired comparisons by PATIENTS

Skin rash


Complete hair loss

Complete hair loss Complete hair loss

Skin rash 76


Skin rash


More discouraging (% of resp.) More discouraging (% of resp.) More discouraging (% of resp.)

Itching or painful skin rash covering >30% of the BS including face for several weeks with lack of energy for several weeks

sever rapy veral daysComplete hair loss

** p < .001 (binomial test)

Q7: Paired comparisons by PHYSICIANS Base: n=120 physicians

7327

937

5941

6832

9010

8812

** ** **

** ** **

a

b

Fig. 1 Paired-comparisonexercise to gauge which adverseevent(s) may be mostdiscouraging to patients in termsof accepting a cancer therapy: apatients’ and b physicians’perspectives. Respondents wereasked to select the morediscouraging AE in a series ofpairs of possible answers.**p < .001 (binomial test)


54% believed that their physical condition during therapyshould not affect their family life or social activities verymuch. 58% of patients agreed that they prefer the most effica-cious therapy regardless of possible AEs. However, 58% alsoagreed that if a cancer therapy induces severe AEs, they wouldprefer a different therapy with less severe AEs. Similar find-ings were obtained from the subgroups of surveyed patientstreated with an EGFR inhibitor (n = 148) and those not treatedwith an EGFR inhibitor (n = 47). When queried specificallyregarding their attitudes towards skin toxicities, 71% of the195 surveyed patients indicated that they were willing to ac-cept skin toxicities as a possible AE, so long as the cancertherapy helps to treat their disease. However, 50% of the pa-tients further acknowledged that these therapy-induced skintoxicities would negatively impact their QoL. Notably, 61%of the patients would choose a more efficacious therapy thatinduces more severe skin toxicities vs a less efficacious ther-apy that induces less severe skin toxicities. This preferencewas significantly more frequent among the 148 surveyed pa-tients who had been treated with an EGFR inhibitor vs the 45patients who had not been treated with an EGFR inhibitor (66vs 45%, respectively; p = .007). Consistent with the patients’preferences, 56% of surveyed physicians would prescribe forthe majority of their patients a more efficacious EGFR inhib-itor therapy that induces more severe skin toxicities vs a lessefficacious therapy with less severe skin toxicities.

Patient and physician risk/benefit trade-off exercise

The results of the hypothetical scenario used to assess pa-tient perception of the risk/benefit trade-offs during cancertherapy are summarized in Fig. 3. 50% of patients werewilling to accept a 56% probability of severe skin toxicities.A similar hypothetical scenario was posed to 118 physi-cians, who were asked to estimate what percent of theirpatients would be willing to accept each risk level of skintoxicities. Interestingly, merely a 32% probability of severeskin toxicities—in addition to nearly all patients developingmild skin toxicities—was deemed as acceptable for 50% oftheir fit, second-line patients with metastatic CRC (ECOGPS of 0 to 1; Fig. 3). Notably, 50% of patients who had self-reported previously experiencing severe skin toxicities(n = 35) were willing to accept a 63% probability of severeskin toxicities, whereas 50% of patients who self-reportednot having experienced skin toxicities (n = 36) were willingto accept only a 55% probability of severe skin toxicities(Fig. 3b). Similarly, patients who had previously been treat-ed with an EGFR inhibitor (n = 145) were willing to accepta higher probability of severe skin toxicities than patientswho had not previously been treated with an EGFR inhib-itor (n = 47) (Fig. 3c). Female and male patients did notdiffer significantly regarding their acceptance of severe skintoxicities.

Table 1 Patients’ and physicians’ perspectives on why itchy or painfulskin toxicities were rated as the most bothersome cancer therapy-relatedadverse event. Patients were asked an open-ended question for whyitching or painful skin rash covering more than 30% of the body

surface including the face would discourage them from accepting thetherapy. Physicians were asked whether risk of itching or painful rashcovering more than 30% of the body surface, including the face, woulddiscourage them from prescribing a therapy

Physicians (n = 115) Patients (n = 179)

Impact on QoL (84%):• More/very bothersome/annoying/burdensome

(than other AEs) (33%)• Impact on QoL (in general) (28%)• Esthetic appearance/visual impact (12%)• Emotional impact (5%)• Impact on social life, skin rash is stigmatizing (10%)• Functional impact (esp. sleeping problems) (10%)• Affects daily life (4%)

Impact on QoL (70%):• More/very bothersome/annoying/burdensome (than other AEs) (20%)• Emotional impact (27%)• Esthetic appearance/visual impact (26%)• Functional impact (sleeping problems, cleaning, dressing) (13%)• Impact on social life, skin rash is stigmatizing (7%)• Affected daily life (4%)

Manageability (46%):• Less manageable than other AEs, insecurity about

handling and outcome (19%)• Lack of patient compliance/non-acceptance of therapy

by patient (15%)• Risk of superinfections and allergic toxicities (14%)• Skin rash treatments frequently required therapy

pauses or discontinuation due to adverse events (13%)

Manageability (18%):• Difficult handling and manageability of skin rash:

(appeared) less manageable than other AEs, insecurity about outcome (9%)• Non-acceptance of therapy by patient (3%)• Risk of superinfections and allergic toxicities (4%)• Skin rash treatments frequently required therapy pauses or discontinuation

due to adverse events (2%)

Pain (10%):• Subjective intolerance towards pain (10%)

Pain (30%):• Painfulness, in general (subjective intolerance of pain) (30%)

Duration and extent of skin rash (0%): Duration and extent of skin rash (24%):• Continuous nature and extent (spread + duration) of skin rash, i.e.,

it seemingly “never ends” (infinite pain, soreness, itching) (24%)

AE adverse event, QoL quality of life


Discussion

A general consideration for all anticancer therapies is the ac-companiment of efficacy by the risk of potential AEs thatimpact QoL. The study presented here specifically focusedon dAEs and their impact on activities of daily living andQoL, as well as insights into how patients and physiciansweigh benefits vs treatment burden of anticancer therapies thatcould potentially cause a skin toxicity. This multinational sur-vey was prompted by a previous structured literature analysis[18], which identified as missing systematic studies that com-pare the impact of dAEs vs other AEs on therapeutic decisionsfrom the patients’ and physicians’ perspectives. The surveyincluded 195 patients and 120 physicians and was conductedto gain deeper insights from both perspectives. The resultingdata suggest that skin toxicities are one of the most impactfulAEs experienced during cancer therapy due to their strongimpact on patient QoL; however, most patients were willing

to accept skin toxicities if they were the anticipated byproductof a more efficacious therapeutic regimen.

It is possible that acceptance of skin toxicity is amplifiedwhen there is high probability that the drug is effective for arelatively long period of time, as is the case with anti-EGFRtherapies in lung and colorectal cancer. Indeed, risk/benefittrade-off analyses confirmed that patients and physicians prefera more efficacious therapy that induces more severe skin toxic-ities vs a less efficacious therapy that induces less severe skintoxicities. Notably, in these risk/benefit trade-off exercises, pa-tients, as compared to physicians, were willing to accept ahigher probability of severe skin toxicities. There were otherimportant differences between patients’ and physicians’ atti-tudes and perceptions regarding risk/benefit trade-offs duringcancer therapy. For example, it is notable that patients wereprincipally discouraged by the pain and the visual and function-al impact of skin toxicities on their QoL, whereas physiciansstated they were discouraged from prescribing a therapy that

Table 2 Patients’ and physician-observed early/initial response to a skin toxicity. Physicians were asked an open-ended question about how theirpatients react when they talk with them about skin toxicities as possible side effects of their therapy. Patients were asked an open-ended question abouttheir first reaction when they experienced skin reactions

Physicians (n = 120) Patients (n = 159)

Acceptance of AEs (63%):• Acceptance since (preventive) treatments are available and

adjustable to individual needs (22%)• Patients tended to accept AEs, although they had concerns because

the extent and severity of AEs was not foreseeable (uncertainty) (14%)• Patients accepted these AEs, but they could not imagine what

consequences these AEs might have (12%)• Patients accepted these AEs (and waited to see what happens),

because they trusted their physicians (12%)• AEs were understood as a sign of efficacy (9%)• Patients accepted treatment as second-line but not as first-line therapy (3%)• Patients accepted treatment because they are used to AEs in general

(from previous therapies) (3%)

Acceptance of AEs (21%):• Acceptable condition, “no worries”;

only mild skin toxicities not/merely affecting QoL (21%)• Certainty that skin rash proved the effectiveness of the therapy (9%)

Negative (5%):• (Some) patients refused treatment due to the (severe) skin toxicity

issue (5%)

Negative (67%):• Embarrassment, disappointment, discomfort about/annoyance with

appearance (esthetic reasons) (19%)• Frustration, nervousness, anger/aggression (11%)• Anxiety/worries (e.g., about effectiveness/adequacy of treatment) (10%)

Expected (0%): Expected (35%):• Understood that these toxicities/were told by the physician/was a

common AE (35%)

Neutral findings (physicians):• Esthetic appearance very important: patients lacked confidence when it came to

cosmetic issues (pimples, etc.) regarding their appearance (demoralization) (14%)• Patients wanted more details on possible AEs and their handling (12%)• No particular reaction; the consent was simply being signed (9%)• Patients were more worried about their cancer than about adverse events (8%)• Patients neglected the fact that skin toxicity may occur; appeared less serious than other toxicities (e.g., liver, kidney) (7%)• (Older) patients did not always understand the concept of AEs; generally felt bothered once they occurred (4%)• Men reacted more positively than women (4%)• Patients were surprised, because they expected typical CT-associated AEs (3%)

AE adverse event, CT chemotherapy, QoL quality of life


elicits skin toxicities because they believe these AEs to be lessmanageable (in addition to impacting patient QoL). This dis-tinction in perceptions suggests that while improvements in themanageability of skin toxicities may make them more accept-able to physicians, patients will continue to view these AEs asdiscouraging unless specific attributes, such as pain, can bereduced or eliminated. These observations are broadly consis-tent with the work of Basch and colleagues, who previouslyreported differences in the grading and perception of skin tox-icities between patients and physicians [19–21].

Taken together, these differences underscore the impor-tance of improved communication between patients and physi-cians: by truly taking into account patients’ viewpoint, there isthe possibility of improving patient QoL. This shared decision-making process allows clinicians and patients tomake decisionstogether in choosing tests and therapies based on data that

weigh risks and benefits with patient values and predilections.Shared decision-making may increase patient choice, clinicaloutcomes, adherence to therapy, and approval of care [22]. Forexample, given the accumulating clinical evidence supportingthe effectiveness of prophylactic management of EGFRinhibitor-attributable skin toxicities [23–30], physicians shouldnot only be well versed regarding this strategy but also becapable of clearly communicating to their patients the existenceof preventative measures/treatments for dAEs and the benefitsof this approach. Speaking more generally, the importance ofimproved patient-physician communication is further rein-forced by our observation that physicians represented the over-whelmingly predominant source of information for the sur-veyed patients regarding their disease; indeed, more than threetimes as many patients treated with EGFR inhibitors reportedreceiving information regarding skin toxicities as a possible AE

Table 3 Patients’ perspectives regarding impact of skin toxicities on quality of life. Patients were asked to specify whether each of the followingconditions applied at a time when the symptoms of the skin toxicities were most severe

% oftotal(n = 158)

% of EGFRinhibitor treated(n = 132)

% of EGFRinhibitor naïve(n = 26)

% ofmild(n = 53)

% ofmoderate(n = 70)

% ofsevere(n = 35)

% ofmale(n = 79)

% offemale(n = 79)

Physical impact

My skin or scalp itched 35 401 8 13 371 631,2 35 34

My skin or scalp was dry or “flaky” 34 391 12 13 401 541 30 38

My skin or scalp felt irritated 34 36 23 11 331 691,2 28 391

I was bothered by sensitivity around myfingernails or toenails

22 241 8 13 23 311 19 24

I was bothered by a change in my skin’ssensitivity to the sun

17 19 8 4 161 401,2 13 22

My eyes were dry 16 17 15 2 171 371,2 9 241

My skin bled easily 11 131 4 0 131 261 10 13

Social-emotional impact

I felt unattractive because of how my skinlooked

26 27 19 9 301 431 17 351

My skin condition affected my mood 22 241 8 8 231 401 15 281

I was embarrassed by skin condition 21 22 15 4 311 261 10 321

I avoided going out in public because of howmyskin looked

18 19 15 2 231 341 10 271

I was bothered by hair loss 9 7 23 15 6 9 9 10

I was bothered by increased facial hair 5 5 4 0 91 6 1 91

Functional impact

My skin condition interfered with my social life 20 21 15 4 201 461,2 11 291

Changes in my skin condition made my lifedifficult

17 17 15 2 191 371 10 241

My skin condition interfered with my ability tosleep

15 17 8 2 191 291 10 201

Sensitivity around my fingernails made itdifficult to perform household tasks

12 12 12 4 9 311,2 10 14

The skin effects from treatment have interferedwith household tasks

6 7 4 4 4 14 4 9

1Higher than “EGFRinhibitor naive”(p < .05)

1Higher than “mild” (p < .05)2Higher than “moderate”

(p < .05)

1Higher than“male”(p < .05)

EGFR epidermal growth factor receptor


of their therapy from their physicians vs any other sources (e.g.,internet, nurses, other patients).

Perhaps our most important finding was the observationthat more patients may be willing to tolerate severe skin tox-icities than their physicians imagined. Notably, this differen-tial risk/benefit assessment was even more pronounced in thesubgroup of surveyed patients who had previously experi-enced severe skin toxicities—and in the subgroup of patientswho had previously been treated with an EGFR inhibitor—perhaps reflecting a “fear of the unknown” in patients whohave not personally experienced skin toxicities andunderscoring the mechanism of anticipatory coping. Asalluded to above, one strength of this study was its abilityto capture the patients’ perspectives, including their atti-tudes concerning weighing benefit vs risk in their cancertherapy decisions. In contrast, a limitation of this study wasthat physicians may have imagined an overall differentpatient cohort (vs the surveyed patients) when asked toestimate the percentage of patients willing to accept a giv-en risk of dAEs during the risk/benefit trade-off exercise.Another limitation was the grouping together of patients

with different tumor types, grouping together of patientstreated with different EGFR inhibitors (including mono-clonal antibodies and tyrosine kinase inhibitors), and, fi-nally, grouping together of patients treated with differentlines of therapy. Additionally, as with every survey, there isthe possibility that the population of respondents was notrepresentative of the overall patient population (potentialself-selection for healthier individuals). Finally, prior tonecessitating reactive therapy and/or drug dosage reduc-tion and interruption, prophylactic therapy seems advisablein every patient receiving EGFR inhibitors, unless contra-indicated, to prevent grade ≥ 2 skin toxicities [13, 32].

Conclusion

In this examination of patients’ perspectives, skin toxicitieswere cited as one of the most discouraging AEs experiencedduring cancer therapy; however, the majority of patients werewilling to accept skin toxicities if they were the anticipated

Ever treated with an EGFR inhibitor?

All pa�entsEGFR inhibitor–treated pa�ents

EGFR inhibitor–naive pa�ents

Absolute number % of total



15A. Statement: I

feel well informed

about my therapy

Total 195 100 148 100 47 100

Completely/ well informed 138 71 108 73 30 64

Moderately informed 49 25 36 24 13 28

Not well informed 8 4 4 3 4 9

15B. Statement: I

feel well informed

about skin

toxicities

Total 195 100 148 100 47 100

Completely/ well informed 125 64 104 70 21 45

Moderately informed 52 27 38 26 14 30

Not well informed 18 9 6 4 12 26

0%

20%

40%

60%

80%

100%

been

info

rmed

via

…

Internet

Brochure ab

out can

cer t

herapy

TV or rad

io reports

88%

28% 22% 20% 17% 9% 6% 3% 3% 1% 0%

EGFR (n=147)

b

aFig. 2 a Patients’ perspectivesregarding how well-informedthey felt about AEs associatedwith their therapy. EGFR,epidermal growth factor receptor.b EGFR inhibitor-treated patientsindicate sources of informationabout skin toxicities as possibleadverse events


Physicians* (n=118)

PATI

ENTS

:

0%

10%

30%

40%

50%

60%

70%

80%

100%

*Ph

0% 10% 30% 40% 50% 60% 70% 80% 100%

0%

10%

40%

70%

80%

100%

0% 10% 40% 70% 80% 100%

P

T

T

0% 0%

a

b

c


byproduct of a more efficacious therapeutic regimen. Therewere important differences between patients’ and physicians’attitudes regarding risk/benefit trade-offs during cancer thera-py, suggesting that improved communication between the twohas the potential to provide value to patients and may improvecancer care and patient QoL. Communicating to patients thecorrelation between rash severity and clinical outcome, as wellas the availability of preventive and reactive therapies fordAEs, must be part of every discussion to minimize anxiety,decrease frequency and severity of toxicities, and maintainQoL.

Acknowledgements M.E.L. is funded in part through the NIH/NCICancer Center Support Grant P30 CA008748. Medical writing assistancewas provided by ClinicalThinking, Inc., Hamilton, NJ, USA, and fundedby Merck KGaA, Darmstadt, Germany.

Compliance with ethical standards

Conflict of interest• B. Tischer: No conflicts to disclose.• M. Kraemer: Employee of Merck KGaA.• P. Ronga: Employee of Merck KGaA.• M. Lacouture: Consulting for AstraZeneca, Boehringer Ingelheim,

Dignitana, Foamix, Genentech, Janssen R&D, Merck Sharpe-Dohme,EMD Serono, Michael’s Mission, Novartis, Oncology TrainingInternational, Quintiles, and RP Pharmaceuticals; research grants fromBerg, Bristol-Myers Squibb, and Roche. This research was funded in partthrough the NIH/Cancer Center Support Grant P30 CA008748.

• M. Bilang: No conflicts to disclose.

Open Access This article is distributed under the terms of the CreativeCommons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits anynoncommercial use, distribution, and reproduction in any medium,provided you give appropriate credit to the original author(s) and thesource, provide a link to the Creative Commons license, and indicate ifchanges were made.

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